The present invention generally relates to a minimally invasive method for administering focused energy, such as adaptive microwave phased array or single applicator hyperthermia, to treat ductal and glandular carcinomas and intraductal hyperplasia, as well as benign lesions such as fibroadenomas and cysts in breast tissue. The breast tissue to be treated may be in either male or female patients and thus, the method according to the invention may treat small to large breasted patients. In addition, the method according to the invention may be used to treat healthy tissue containing undetected microscopic pathologically altered cells of high-water content to prevent the occurrence of or the recurrence of cancerous, pre-cancerous or benign breast lesions.
In order to treat primary breast cancer with hyperthermia, it is necessary to heat large volumes of tissue such as a quadrant or more of the breast. It is well known that approximately 90% of all breast cancers originate within the lactiferous ductal tissues (milk ducts) with much of the remaining cancers originating in the glandular tissue lobules (milk sacks) (Harris et al., The New England Journal of Medicine, Vol. 327, pp. 390-398, 1992). Breast carcinomas often involve large regions of the breast for which current conservative treatments have a significant risk of local failure. Schnitt et al., Cancer, Vol. 74 (6) pp. 1746-1751, 1994. With early-stage breast cancer, known as T1 (0-2 cm) or T2 (2-5 cm) cancers, the entire breast is at risk and often is treated with breast-conserving surgery combined with full-breast irradiation to destroy any possible microscopic (not visible to the human eye without the aid of a microscope or mammography) cancer cells in the breast tissue (Winchester et al., CA-A Cancer Journal for Clinicians, Vol. 42, No. 3, pp. 134-162, 1992). The successful treatment of invasive ductal carcinomas with an extensive intraductal component (EIC) where the carcinomas have spread throughout the ducts is particularly difficult, since large portions of the breast must be treated. Over 800,000 breast needle biopsies of suspicious lesions are performed annually in the United States with approximately 205,000 cases of cancer detected, the rest being nonmalignant such as fibroadenomas and cysts. The American Cancer Society estimates that in 2002 the number of new cases of breast cancer in the United States will be 203,500 cases in female patients and 1,500 cases in male patients. (Cancer Facts and Figures 2002, American Cancer Society, Atlanta, Ga., p. 4, 2002).
The use of heat to treat breast carcinomas can be effective in a number of ways, and in most cases the heat treatment must be capable of reaching, simultaneously, widely separated areas within the breast. Heating large volumes of the breast can destroy many or all of the microscopic carcinoma cells in the breast, and reduce or prevent the recurrence of cancerxe2x80x94the same approach is used in radiation therapy where the entire breast is irradiated with x-rays to kill all the microscopic cancer cells. Heating the tumor and killing a large percentage or all of the tumor cells prior to lumpectomy may reduce the possibility of inadvertently seeding viable cancer cells during the lumpectomy procedure, thus reducing local recurrences of the breast. Sometimes, the affected breast contains two or more tumor masses distributed within the breast, known as multi-focal cancer, and again the heating field must reach widely separated regions of the breast. Locally advanced breast carcinomas (known as T3) (Smart et al., A Cancer Journal for Clinicians, Vol. 47, pp. 134-139, 1997) can be 5 cm or more in size and are often treated with mastectomy. Pre-operative hyperthermia treatment of locally advanced breast cancer may shrink the tumor sufficiently to allow a surgical lumpectomy procedure to be performedxe2x80x94similar to the way pre-operative chemotherapy is currently used. Pre-operative hyperthermia treatment of locally advanced breast cancer may destroy the tumor completely, eliminating the need of any surgery.
It is well known that microwave energy can preferentially heat high-water content tissues such as breast tumors and cysts, compared to the heating that occurs in low-water content tissue such as fatty breast tissue. Many clinical studies have established that hyperthermia (elevated temperature) induced by electromagnetic energy absorption in the microwave band, significantly enhances the effect of radiation therapy in the treatment of malignant tumors in the human body (Valdagni, et al., International Journal of Radiation Oncology Biology Physics, Vol. 28, pp. 163-169, 1993; Overgaard et al., International Journal of Hyperthermia, Vol. 12, No. 1, pp. 3-20, 1996; Vernon et al., International Journal of Radiation Oncology Biology Physics, Vol. 35, pp. 731-744, 1996; van der Zee et al, Proceedings of the 7th International Congress on Hyperthermic Oncology, Rome, Italy, April 9-13, Vol. II, pp. 215-217, 1996; Falk and Issels, xe2x80x9cHyperthermia in Oncologyxe2x80x9d, International Journal of Hyperthermia, Vol. 17, No. 1, 2001, pp. 1-18.). Radio-resistant cells such as S-phase cells can be killed directly by elevated temperature (Hall, Radiobiology for the Radiologist, 4th Edition, J B Lippincott Company, Philadelphia, pp. 262-263, 1994; Perez and Brady, Principles and Practice of Radiation Oncology, Second Edition, J B Lippincott Company, Philadelphia, pp. 396-397, 1994). Hyperthermia treatments with microwave radiating devices are usually administered in several treatment sessions, in which the malignant tumor is heated to about 43xc2x0 C. for about 60 minutes. It is known that the amount of time to kill tumor cells decreases by a factor of two for each degree increase in temperature above about 43xc2x0 C. (Sapareto, et al., International Journal of Radiation Oncology Biology Physics, Vol. 10, pp. 787-800, 1984). Thus, a 60-minute treatment at 43xc2x0 C. can be reduced to only about 15 minutes at 45xc2x0 C., which is often referred to as an equivalent dose (t43xc2x0 C.equivalent minutes). It has also been clinically established that thermotherapy enhances the effect of chemotherapy (Falk and Issels, 2001). During treatments with noninvasive microwave applicators, it has proven difficult to heat semi-deep tumors adequately while preventing surrounding superficial healthy tissues from incurring pain or damage due to undesired hot spots. The specific absorption rate (SAR) in tissue is a common parameter used to characterize the heating of tissue. The SAR is proportional to the rise in temperature over a given time interval, and for microwave energy the SAR is also proportional to the electric field squared times the tissue electrical conductivity. The units of absolute SAR are watts per kilogram.
Non-coherent-array or non-adaptive phased array hyperthermia treatment systems typically can heat superficial tumors, but are restricted in their use for heating deep tumors or deep tissue, because they tend to overheat intervening superficial tissues, which can cause pain and/or burning. Single applicator hyperthermia treatments with the assignee of the instant invention""s TEM air-cooled microwave waveguide applicator have been successful in treating superficial cancers including recurrent breast cancer (chest wall cancer) (Shindig, H. et al., xe2x80x9cClinical Experience with Hyperthermia in Conjunction with Radiation Therapyxe2x80x9d Oncology, Vol. 50, pp. 353-361, 1993). The first published report describing a non-adaptive phased array for deep tissue hyperthermia was a theoretical study (von Hippel, et al., Massachusetts Institute of Technology, Laboratory for Insulation Research, Technical Report 13, AD-769 843, pp. 16-19, 1973). U.S. Pat. No. 3,895,639 to Rodler describes two-channel and four-channel non-adaptive phased array hyperthermia circuits. Recent developments in hyperthermia systems effectively target the delivery of heat to deep tissue using adaptive phased array technology originally developed for microwave radar systems (Skolnik, Introduction to Radar Systems, Second Edition, McGraw-Hill Book Company, 1980 pp. 332-333; Compton, Adaptive Antennas, Concepts and Performance, Prentice Hall, N.J., p. 1, 1988; Fenn, IEEE Transactions on Antennas and Propagation, Vol. 38, number 2, pp. 173-185, 1990; U.S. Pat. Nos. 5,251,645; 5,441,532; 5,540,737; 5,810,888).
Bassen et al., Radio Science, Vol. 12, No. 6(5), November-December 1977, pp. 15-25, shows that an electric-field probe can be used to measure the electric-field pattern in tissue, and in particular, shows several examples in which the measured electric-field has a focal peak in the central tissue. This paper also discusses a concept for real-time measurements of the electric-field in living specimens. However, Bassen et al. did not develop the concept of measuring an electric-field using real-time with an electric-probe to adaptively focus a phased array.
An adaptive phased array hyperthermia system uses F-field feedback measurements to focus its microwave energy on deep tissue while simultaneously nullifying any energy that might overheat surrounding healthy body tissue. Pre-clinical studies indicate that adaptive microwave phased arrays have the potential for delivering deep heat while sparing superficial tissues from excessive temperatures in deep torso (Fenn, et al., International Journal of Hyperthermia, Vol. 10, No. 2, March-April, pp. 189-208, 1994; Fenn et al., The Journal of Oncology Management, Vol. 7, number 2, pp. 22-29, 1998) and in breast (Fenn, Proceedings of the Surgical Applications of Energy Sources Conference, 1996; Fenn et al., International Journal of Hyperthermia, Vol. 15, No. 1, pp. 45-61, 1999; Gavrilov et al., International Journal of Hyperthermia, Vol. 15, No. 6, pp. 495-507, 1999).
The most difficult aspect of implementing hyperthermia in deep breast tissues, with microwave energy, is producing sufficient heating at a predetermined depth while protecting the skin from burns. Noninvasive multiple applicator adaptive microwave phased arrays with invasive and noninvasive electric field probes can be used for producing an adaptively focused beam at the tumor position with adaptive nulls formed in healthy tissues as described in U.S. Pat. Nos. 5,251,645, 5,441,532, 5,540,737, and 5,810,888, all of which are incorporated herein by reference. Ideally, a focused microwave radiation beam is concentrated at the tumor with minimal energy delivered to surrounding healthy tissue. To control the microwave power during treatment, a temperature-sensing feedback probe (Samaras et al., Proceedings of the 2nd International Symposium, Essen, Germany, Jun. 2-4, 1977, Urban and Schwarzenberg, Baltimore, 1978, pp. 131-133) is inserted into the tumor, however, it is often difficult to accurately place the probe in the tumor. An additional difficulty occurs in delivering hyperthermia to carcinoma spread throughout the ductal or glandular tissues of the breast, because of a lack of a well defined target position for the temperature-sensing feedback probe. In other situations, it is desirable simply to avoid inserting probes (either temperature or E-field) into the breast tissue in order to reduce the risk of infection or spreading the cancer cells when the probe passes through the tumor region.
The standard of medical care for treating benign cysts that have been detected varies from doing nothing to draining the cysts. The medically accepted position of not treating the cysts exists because the only known method of removing cysts involves invasive surgery. The alternative to surgically cutting and removing a cyst is draining the cyst. Draining the cyst is achieved by piercing the cyst and removing the liquid inside the cyst. While this method may temporarily relieve the pain associated with the cyst, the cyst may grow back if the draining procedure failed to remove the entire cyst. Therefore, there is a need for a non-invasive removal of these benign cysts.
The above shortcomings are solved by the Assignee of the instant invention""s method for heating cancerous conditions of the breast which comprises the steps of inserting an E-field probe sensor in the breast, monitoring temperatures of the skin surface, orienting two microwave applicators on opposite sides of the breast, setting the initial microwave power and phase delivered to each microwave applicator in order to focus the field at the inserted E-field sensor, adjusting the microwave power to be delivered to the breast based on the monitored skin temperatures, and monitoring the microwave energy dose delivered to the breast being treated and completing the treatment when a desired total microwave energy dose has been delivered by the microwave applicators.
Moreover, the above method by the Assignee of the instant invention has application in situations such as when there is no well-defined position to place the temperature feedback sensor, or when it is desirable to avoid inserting a temperature probe into the breast tissue. Only a single minimally invasive E-field sensor is required in the preferred method taught by the Assignee. Thus, in the case of advanced breast cancer (e.g., a tumor 5-8 cm), this method can destroy a significant portion of the breast cancer cells and shrink the tumor or lesion (i.e., thermal downsizing to e.g., 2-3 cm) thereby replacing a surgical mastectomy with a surgical lumpectomy. In the alternative, the entire advanced breast cancer lesion can be destroyed and no surgery may be required. In early-stage breast cancer or for small breast lesions, the Assignee""s method may destroy all of the breast cancer cells or benign lesions with heat (i.e., a thermal lumpectomy) thereby avoiding a surgical lumpectomy. In addition, the method can be used to enhance radiation therapy or for targeted drug delivery with thermosensitive liposomes as described in U.S. Pat. No. 5,810,888 and/or targeted gene therapy delivery. The assignee""s method may be used with a recently developed temperature sensitive liposome formulation with chemotherapy agents such as doxorubicin as described in U.S. Pat. No. 6,200,598 xe2x80x9cTemperature Sensitive Liposomal Formulation,xe2x80x9d Mar. 13, 2001 to Needham, in which drug agents are released at temperatures of approximately 39 to 45 degrees Celsius.
The assignee""s method described above destroys the cancerous cells while sparing the normal glandular, ductal, connective, and fatty tissue of the breast. Thus, a thermal lumpectomy according to the invention avoids damage to such healthy tissue and is a breast conservation technique.
While the Assignee""s method may be achieved employing the adaptive microwave phased array technology, focussing energy, in general, may be used to heat and ablate an area of tissue. The focused energy may include electromagnetic waves, ultrasound waves or waves at radio frequency. That is, any energy that can be focused to heat and ablate an area of tissue.
While the Assignee""s method described above non-invasively removes cysts from breast tissue, other problems arise due to the externally focused microwaves and the mechanical pressure employed to compress the breast tissue. Thus, improvements in safety of such a non-invasive thermotherapy cancer treatment are needed.
Applicants overcome shortcomings in the prior art with their inventive method for treating cancerous or benign conditions of an organ or superficial areas of a body by selective irradiation of the effected tissue with focused energy. The method according to the invention may include the steps of inserting an E-field probe sensor to an appropriate depth in the organ tissue (if two or more energy applicators employed), monitoring temperatures of the skin surface adjacent the organ or portion of the body to be treated, positioning at least one energy applicator (i.e., one or more applicators) around the organ or body to be treated, setting the initial power level delivered to each energy applicator, setting the initial relative phase delivered to each energy applicator to focus the energy at the E-field probe positioned in the organ tissue (if two or more energy applicators employed), delivering energy to the at least one energy applicator to selectively irradiate the organ tissue or tissue of the body to be treated with focused energy and treat at least one of cancerous and benign conditions of the organ or body to be treated, adjusting the level of power to be delivered to each energy applicator during treatment based on the monitored skin temperatures, monitoring the energy delivered to the at least one energy applicator, determining total energy delivered to the at least one energy applicator and displaying the total energy in real time during the treatment, and completing the treatment when the desired total energy dose has been delivered by the energy applicators to the organ. The preferred organ to be treated is the breast and in a preferred method, the energy applicators may be positioned in a ring about the breast (or other organ).
According to the invention, a preferred method for treating cancerous or benign conditions of an organ or body to be treated by selective irradiation of the organ or body tissue with energy may include the steps of injecting a substance that enhances heating to an appropriate depth in the organ tissue or tissue of the body to be treated, monitoring temperatures of the skin surface adjacent the organ or body to be treated, positioning at least one energy applicator about the organ or body to be treated, setting the initial power level delivered to each at least one energy applicator, delivering energy to the at least one energy applicator to selectively irradiate the organ or body tissue with energy and treat at least one of cancerous and benign conditions of the organ or body, adjusting the level of power to be delivered to each at least one energy applicator during treatment based on the monitored skin temperatures, monitoring the energy delivered to the at least one energy applicator, determining total energy delivered to the at least one energy applicator and displaying the total energy in real time during the treatment, and completing the treatment when the desired total energy dose has been delivered by the at least one energy applicator to the organ or body to be treated. That is, Applicants envision that the method according to the invention may be achieved with a single applicator and may be any energy that can be focussed on the cancerous or benign conditions of the organ or body to be treated.
In accordance with the invention, microwave absorbing pads and metallic shielding are attached to microwave thermotherapy applicators and to the breast compression paddles. These safety precautions added to the Assignee""s method reduce the electric-field intensity and temperature outside the primary microwave applicator aperture field in the vicinity of the base of the breast, chest wall region, and head and eyes during adaptive phased array thermotherapy in compressed breast tissue for breast tumor (malignant or benign) treatment.
In order to minimize the amount of invasive skin entry points, combined E-field and temperature sensors within a single catheter are used with the Assignee""s method. As a result, only a single minimally invasive skin entry point is required resulting in improved patient comfort and reducing the risk of infection. In an alternate embodiment with a single microwave applicator, an E-field sensor is not required, as temperature monitoring controls the power delivered to the applicator. Thus, it is not necessary to have an invasive skin entry point if surface temperature sensors are employed.
Additionally, adaptive microwave phased array thermotherapy can be used as a heat-alone treatment for early-stage breast cancer. Alternatively, adaptive microwave phased array thermotherapy can be used in combination with a chemotherapy regimen and/or gene based modifiers for treatment of the primary breast tumor in locally advanced breast cancer. Alternatively, the breast thermotherapy heat-alone treatment can be used as a pre-surgical tool to reduce the rate of second or third incisions (additional surgery) for lumpectomy patients. An additional use of adaptive microwave thermotherapy can be in improved breast cancer prevention in which thermotherapy is used with Tamoxifen or other antiestrogen drug for blocking estrogen from binding to the estrogen receptors of breast carcinomas and for direct cancer cell kill by heat.
In another method according to the invention, a single air-cooled energy applicator positioned over the breast of a patient would be used to heat the breast tissue with the temperature of the breast tissue being measured by either an inserted temperature probe or temperature sensors attached to the skin of the breast. This method could be used in cases where the breast does not extend into an aperture formed by two or more energy applicators (in a so-termed small breasted patient), or the tumor or tissue to be treated is located at the edge of the aperture formed by the applicators. Depending upon the position of the tumor or tissue to be treated, the patient may lie in either prone or supine to receive treatment from the single air-cooled energy applicator.
The breast tissue may be compressed toward the chest wall by means of a tubular shaped material or band that encircles the patient""s torso region. The width of the material may correspond to the width of the breast being treated so that it flattens the breast thereby reducing blood flow in the vicinity of the tumor or tissue to be treated and reducing the depth of the tumor or tissue to be treated relative to the skin.
In yet another method according to the invention, the single applicator would be positioned over the breast or superficial areas having a benign or cancerous tumor, such as the head, neck, torso, arms or legs so that emitted energy is aimed at one of a tumor (treatment for cancer or benign conditions) and an upper portion of the breast where a majority of breast cancers occur (prevention of cancer). Applicants envision a non-invasive temperature monitoring system although an invasive temperature probe may be employed depending upon the location of the treated tissue and ability to achieve the therapeutic temperature at the treated tissue. For example, with a single applicator, one or more surface temperature sensors may be used to monitor the skin temperature and the output of which then would be used as feedback signals to control the microwave power level delivered to a microwave applicator. A microwave energy dose of up to approximately 360 kilojoules, preferably about 90 kilojoules (e.g., 200 Watts of microwave power for about 30 minutes, preferably about 50 Watts of microwave power for about 30 minutes) may be administered to the breast to be treated to destroy a tumor prior to lumpectomy or microscopic breast cancer cells following a lumpectomy, for example.
Certain proteins are known to allow cancer cells to spread, whereas other proteins prevent cancer cells from spreading. In the case of breast cancer, high levels of the anti-apoptotic protein Bcl-2 are found in early-stage breast cancers, particularly those cancer cells that are estrogen receptor (ER) positive and tumor suppressor protein p53 immunonegative. The Bcl-2 family of proteins reduces programmed cell death (known as apoptosis) in breast cancer cells so that the cancer cells do not die fast enough and subsequently spread (Zapata, et al, xe2x80x9cExpression of Multiple Apoptosis-Regulatory Genes in Human Breast Cancer Cell Lines and Primary Tumorsxe2x80x9d, Breast Cancer Research and Treatment, Vol. 47; pages 129-140, 1998). Other anti-apoptotic proteins in breast cancer are Bcl-XL, Mcl-1, and BAG-1. It is assumed that pro-apoptotic proteins such as Bax, Bak, and CPP32 that prevent cancer cells from spreading are not affected by the heat treatment. Similar proteins are associated with other types of tumors and Applicants"" invention envisions treatments of various kinds of cancer. Applicants theorize that the use of heat achieved by the at least one energy applicator, according to the invention, selectively heats anti-apoptosis proteins in the treated body site or organ thereby promoting and increasing the production of protein inhibitors for the anti-apoptosis proteins at the tumor area, which will suppress the anti-apoptosis proteins and suppress the spread of cancer and other associated conditions or diseases. That is, the heat formed by providing power to the at least one energy applicator kills the anti-apoptosis proteins or causes the production of protein inhibitors targeted at the anti-apoptosis proteins that suppress the growth of cancer and other conditions.
The selective irradiation according to the method produces sufficient heat to create DNA damage and it is theorized that the protein, which is responsible for the ability of the cancer cells to repair themselves, is removed or deleted from its association with the DNA molecule during the heat achieved by the one or more energy applicators according to the invention. As a result of the removal of this protein, cancerous cells should die naturally by the apoptosis process. Cytotoxins or substances that poison living cells are associated with radiation, chemotherapy, or heat. It is theorized that these cytotoxins damage the DNA molecule deleting the protein responsible for cell repair. Removal or deletion of the protein responsible for repair will enhance the ability of the cytotoxins to cause apoptosis and necrosis of cancerous cells.
Applicants further envision a method for destroying or melting away fat and other undesired tissues for cosmetic purposes. For example, cellulite, which is currently treated by an invasive and painful liposuction procedure, may be successfully removed from legs of a body by injecting a material with high electrical conductivity, such as a saline solution into the low conductivity fat and then emitting microwave radiation or other energy toward the body to melt the fat deposits. Cellulite is a mass or deposit of fat and fibrous tissue that causes dimpling of the overlying skin. Loose fibrous tissue together with the fat may cause the lumpy appearance of cellulite. The exposure to microwave radiation or other energy toward the body may shrink the connective tissues thereby tightening the loose tissue and smoothing out the unsightly lumpy appearance. To localize or pinpoint the energy to be absorbed by the cellulite or other undesired tissue to be treated, small doses of a material with a higher electrical conductivity than the surrounding tissues can be injected into a preselected area of cellulite or other undesired tissue of a body so that the energy is preferentially absorbed at the preselected area or areas thereby enhancing the heating of the preselected area. The injection of the higher electrical conductivity material may be done up to about a half hour before the exposure to microwave radiation or other energy. A higher electrical conductivity material may be a saline solution or a solution with metallic compounds. The injection of the material with a higher electrical conductivity may be used in combination with other drugs or medicaments to enhance heating of the preselected area. Depending upon the area of the body to be treated, the at least one energy applicator may be external to the body or inserted in a natural cavity of the body (e.g., transurethral, transrectal). A microwave blanket or other protective covering may be used to protect the body area from stray energy.
The exposure to microwave radiation or other energy theoretically should cause the fatty deposits injected with a higher electrical conductivity material to become denatured and/or fluid. If the fat is denatured, it theoretically may be reabsorbed naturally by the body and thus, may not need to be removed. In that situation, the lumps may be smoothed out by wrapping the area of the body that was exposed to heat created by microwave radiation or other energy. The wrapping of the body would have sufficient pressure to postmold or preshape the body that was treated. However, if the fat is to be removed, the more liquid fat would be easier to remove from the area being treated than known liposuction procedures via a vacuum-assisted suction. Long tubes or needles like those associated with known liposuction procedures may be used to suction the melted fat away from the area being treated. Since the fat treated by exposure to microwave radiation or other energy will be fluid or liquid in form, the removal procedure should be easier, quicker and less painful than known liposuction procedures, which attempts to use suction to remove solid fat deposits.
Further objectives and advantages will become apparent from a consideration of the description and drawings.